Dopamine is one of the principal neurotransmitters in the central nervous system (CNS), where it is involved with motor function, perception, arousal, motivation and emotion. Abnormalities in dopaminergic neurotransmission have been implicated in various neurological and psychiatric disorders, including Parkinson's disease, depression, attention deficit disorder (ADD) and drug dependence.
The major pathway by which monoamines are inactivated is by being transported back into the cell that released them via specific transporter proteins (i.e. serotonin, norepinephrine and dopamine transporter proteins). The dopamine transporter protein (DAT) is the carrier molecule which transports dopamine across the synaptic membrane (Hitri et al., Clinical Neuropharmacology, 1994, 17, 1-22). The human dopamine transporter protein was recently cloned and shown to have several binding sites, including a binding site for cocaine (Giros et al., Mol. Pharmacol., 1992, 42, 383-390).
In the last decade, the molecular site of cocaine's addictive properties has been determined to be the DAT (Kuhar et al., TIPS, 1991, 14, 299-302). It was originally proposed that cocaine was a competitive inhibitor of dopamine uptake, coincident with cocaine and dopamine having common binding domains on the DAT. However, recent evidence suggests that dopamine and cocaine binding sites on the DAT are distinct (Kityama et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 7782-7785).
Partial agonists and/or antagonists at the cocaine site on the DAT may show efficacy in treating cocaine addiction. Importantly, several compounds which bind to the cocaine binding site have been shown to block the effects of cocaine in vivo. For example, GBR 12909 has been shown to attenuate cocaine-induced activation of mesolimbic dopamine neurons in rat (Baumann et al., J. Pharm. Exp. Therap., 1994, 271, 1216-1222). Accordingly, compounds which bind to the cocaine site but do not inhibit dopamine uptake (i.e. a cocaine antagonist) may have utility in the treatment of cocaine addiction (Carroll et al., Pharmaceutical News, 1994, 1, 11-17).
Compounds which bind at the cocaine site and are not completely selective may inhibit dopamine reuptake. Studies have demonstrated that such compounds are effective or potentially effective in treating neuropsychiatric disorders characterized by abnormal dopaminergic neurotransmission, including Parkinson's disease (Mayer et al., MPTP: Neurotoxin Prod. Parkinsonian Syndr., Markey et al. (Ed.), 1985, 585-589); depression (Nielsen et al., Adv. Biosci., 1990, 77, 101-108; Randrup et al., Psychopharmacology, 1977, 52, 73-77; Halaris et al., Biochem. Pharmacol., 1975, 24, 1896-1897); attention deficit disorder (ADD) (Volkow et al., Arch. Gen. Psychiatry, 1995, 52, 456-63); and compulsive disorders (Goodman et al., International Clinical Psychopharmacology, 1992, 7(Suppl. 1), 35). Although dopamine uptake inhibitors have been proposed for treating drug dependence in general (Caine et al., Science, 1993, 260, 1814), there has been a dearth of evidence supporting their effectiveness in treating alcohol or nicotine addiction. At best, dopamine uptake inhibitors have been reported to antagonize the behavioral effects of nicotine in mice (Lerner-Marmarosh et al., Life Sci., 1995, 56, PL67-70).
Besides drug dependence, deficits in dopamine function have also been associated with pathological gambling, ADD, Tourette's syndrome, compulsive overeating and obesity. In fact, a common genetic anomaly in the dopamine D.sub.2 receptor has been found among people with alcoholism, cocaine dependence, nicotine dependence, pathological gambling, attention deficit disorder (ADD), Tourette's syndrome, compulsive overeating and obesity (U.S. Pat. No. 5,621,133).
Like ethanol and other drugs of abuse, food can produce euphoria or pleasure when consumed. Although the precise localization and specificity of the reinforcing properties of these substances are under debate, there is general accord that they are manifested in the dopaminergic reward pathways of the brain (Hoebel, Amer. J. Clin. Nutrit., 1985, 42, 1133-1150). Evidence that the dopaminergic system may be implicated in obesity is suggested from studies showing the effectiveness of amphetamine-like drugs in weight loss (Scoville, Bray (Ed.), Obesity in Perspective, 1975, 441-443).
Pathological gambling also has many affinities to drug dependence. Clinicians have remarked on the similarity between the aroused euphoric state of the gambler and the "high" of the cocaine addict or substance abuser. Pathological gamblers express a distinct craving for the "feel" of gambling; they develop tolerance in that they need to take progressively greater risks and make progressively larger bets to reach a desired level of excitement; and they experience withdrawal-like symptoms (anxiety and irritability) when no "action" is available (Volberg et al., Amer. J. Psychiatry, 1988, 145, 502-505).
Attention deficit disorder (ADD) manifests itself primarily in children. The symptoms include an inability to remain focused on a particular task for an extended period of time (Funk et al., Pediatrics, 1993, 91, 816-819). A variety of drugs have been prescribed for this disease, including dextroamphetamine and methylphenidate. Methylphenidate appears to exert its effects by inhibiting the dopamine transporter, more specifically by binding to the cocaine site on the dopamine transporter (Volkow et al., Arch. Gen. Psychiatry, 1995, 52, 456-63). As a result, compounds which have a similar mode of action at this binding site may also show efficacy in this disease.
Tourette's syndrome is an autosomal dominant neuropsychiatric disorder characterized by a range of neurological and behavioral symptoms, including (i) the onset of the disorder before the age of 21 years, (ii) multiple motor and vocal tics, (iii) variance in the clinical phenomenology of the tics, and (iv) occurrence of quasi daily tics throughout a period of time exceeding a year. Motor tics generally include eye blinking, head jerking, shoulder shrugging and facial grimacing; while vocal tics include throat clearing, sniffling, yelping, tongue clicking and uttering words out of context. Recent studies have linked Tourette's syndrome with ADD. In studies of the two disorders, it was found that 50% to 80% of the people with Tourette's syndrome also had ADD. Furthermore, an increased number of relatives of individuals with Tourette's syndrome also had ADD (Knell et al, Journal of Clinical Psychiatry, 1993, 54, 331-337). The strong correlation between these disorders have led some researchers to propose that Tourette's syndrome is severe form of ADD (Comings et al., Journal of Clinical Psychiatry, 1989, S1, 275-280; Comings, Annals of Clinical Psychiatry, 1990, 6, 235-247).
There are currently no medications which effectively treat cocaine addiction. Accordingly, a need exists for compounds having an affinity for the cocaine site on a dopamine transporter protein (DAT), without inhibiting dopamine uptake, to aid in the treatment of cocaine addiction.
A further need exists for compounds which inhibit dopamine uptake to aid in the treatment of neurological disorders characterized by abnormal dopaminergic neurotransmission, particularly compulsive disorders such as drug dependence, eating disorders, pathological gambling and Tourette's syndrome.
The applicant has discovered new pharmaceutical compositions and new methods for treating the above described diseases, disorders and conditions using pyrrolidine derivatives.